Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

Current Applications of PET/MR: Part I: Technical Basics and Preclinical/Clinical Applications.

Positron emission tomography/magnetic resonance (PET/MR) imaging has gone through major hardware improvements in recent years, making it a reliable state-of-the-art hybrid modality in clinical practice. At the same time, image reconstruction, attenuation correction, and motion correction algorithms have significantly evolved to provide high-quality images. Part I of the current review discusses technical basics, pre-clinical applications, and clinical applications of PET/MR in radiation oncology and head and neck imaging. PET/MR offers a broad range of advantages in preclinical and clinical imaging. In the preclinic, small and large animal-dedicated devices were developed, making PET/MR capable of delivering new insight into animal models in diseases and facilitating the development of methods that inform clinical PET/MR. Regarding PET/MR's clinical applications in radiation medicine, PET and MR already play crucial roles in the radiotherapy process. Their combination is particularly significant as it can provide molecular and morphological characteristics that are not achievable with other modalities. In addition, the integration of PET/MR information for therapy planning with linear accelerators is expected to provide potentially unique biomarkers for treatment guidance. Furthermore, in clinical applications in the head and neck region, it has been shown that PET/MR can be an accurate modality in head and neck malignancies for staging and resectability assessment. Also, it can play a crucial role in diagnosing residual or recurrent diseases, reliably distinguishing from oedema and fibrosis. PET/MR can furthermore help with tumour characterization and patient prognostication. Lastly, in head and neck carcinoma of unknown origin, PET/MR, with its diagnostic potential, may obviate multiple imaging sessions in the near future.

Magnetic resonance metrics for identification of cuprizone-induced demyelination in the mouse model of neurodegeneration: a review.

Neurodegenerative disorders, including Multiple Sclerosis (MS), are heterogenous disorders which affect the myelin sheath of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) provides a non-invasive method for studying, diagnosing, and monitoring disease progression. As an emerging research area, many studies have attempted to connect MR metrics to underlying pathophysiological presentations of heterogenous neurodegeneration. Most commonly, small animal models are used, including Experimental Autoimmune Encephalomyelitis (EAE), Theiler's Murine Encephalomyelitis (TMEV), and toxin models including cuprizone (CPZ), lysolecithin, and ethidium bromide (EtBr). A contrast and comparison of these models is presented, with focus on the cuprizone model, followed by a review of literature studying neurodegeneration using MRI and the cuprizone model. Conventional MRI methods including T1 Weighted (T1W) and T2 Weighted (T2W) Imaging are mentioned. Quantitative MRI methods which are sensitive to diffusion, magnetization transfer, susceptibility, relaxation, and chemical composition are discussed in relation to studying the CPZ model. Overall, additional studies are needed to improve both the sensitivity and specificity of MRI metrics for underlying pathophysiology of neurodegeneration and the relationships in attempts to clear the clinico-radiological paradox. We therefore propose a multiparametric approach for the investigation of MR metrics for underlying pathophysiology.

Myocardial glucose suppression may interfere with the detection of inflammatory cells with FDG-PET as suggested in a canine model of myocardial infarction.

BACKGROUND: After myocardial infarction, fibrosis and an ongoing dysregulated inflammatory response have been shown to lead to adverse cardiac remodeling. FDG PET is an imaging modality sensitive to inflammation as long as suppression protocols are observed while gadolinium enhanced MRI can be used to determine extracellular volume (ECV), a measure of fibrosis. In patients, glucose suppression is achieved variously through a high fat diet, fasting and injection of heparin. To emulate this process in canines, a heparin injection and lipid infusion are used, leading to similar fatty acids in the blood. The aim of this study was to examine the effect of glucose suppression on the uptake of FDG in the infarcted myocardial tissue and also on the determination of ECV in both the infarcted tissue and in the myocardium remote to the zone of infarction during a long constant infusion of FDG and Gd-DTPA. RESULTS: Extracellular volume was affected neither by suppression nor the length of the constant infusion in remote and infarcted tissue. Metabolic rate of glucose in infarcted tissue decreased during and after suppression of glucose uptake by lipid infusion and heparin injection. An increase in fibrosis and inflammatory cells was found in the center of the infarct as compared to remote tissue. CONCLUSION: The decrease in the metabolic rate of glucose in the infarcted tissue suggests that inflammatory cells may be affected by glucose suppression through heparin injection and lipid infusion.

Probing Evidence of Cerebral White Matter Microstructural Disruptions in Ischemic Heart Disease Before and Following Cardiac Rehabilitation: A Diffusion Tensor MR Imaging Study.

BACKGROUND: Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear. PURPOSE: To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event. STUDY TYPE: Retrospective. POPULATION: Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years). FIELD STRENGTH/SEQUENCE: 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event. ASSESSMENT: Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure. STATISTICAL TESTS: Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P < 0.05 (FWE-corrected). RESULTS: TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR. DATA CONCLUSION: In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BACKGROUND: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. METHODS: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. DISCUSSION: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. TRIAL REGISTRATION: NCT05230251 (ClinicalTrials.gov).

Complementary early-phase magnetic particle imaging and late-phase positron emission tomography reporter imaging of mesenchymal stem cells in vivo.

Stem cell-based therapies have demonstrated significant potential in clinical applications for many debilitating diseases. The ability to non-invasively and dynamically track the location and viability of stem cells post administration could provide important information on individual patient response and/or side effects. Multi-modal cell tracking provides complementary information that can offset the limitations of a single imaging modality to yield a more comprehensive picture of cell fate. In this study, mesenchymal stem cells (MSCs) were engineered to express human sodium iodide symporter (NIS), a clinically relevant positron emission tomography (PET) reporter gene, as well as labeled with superparamagnetic iron oxide nanoparticles (SPIOs) to allow for detection with magnetic particle imaging (MPI). MSCs were additionally engineered with a preclinical bioluminescence imaging (BLI) reporter gene for comparison of BLI cell viability data to both MPI and PET data over time. MSCs were implanted into the hind limbs of immunocompromised mice and imaging with MPI, BLI and PET was performed over a 30-day period. MPI showed sensitive detection that steadily declined over the 30-day period, while BLI showed initial decreases followed by later rapid increases in signal. The PET signal of MSCs was significantly higher than the background at later timepoints. Early-phase imaging (day 0-9 post MSC injections) showed correlation between MPI and BLI data (R2 = 0.671), while PET and BLI showed strong correlation for late-phase (day 10-30 post MSC injections) imaging timepoints (R2 = 0.9817). We report the first use of combined MPI and PET for cell tracking and show the complementary benefits of MPI for sensitive detection of MSCs early after implantation and PET for longer-term measurements of cell viability.

Glucose Infusion Induced Change in Intracellular pH and Its Relationship with Tumor Glycolysis in a C6 Rat Model of Glioblastoma.

INTRODUCTION: The reliance on glycolytic metabolism is a hallmark of tumor metabolism. Excess acid and protons are produced, leading to an acidic tumor environment. Therefore, we explored the relationship between the tumor glycolytic metabolism and tissue pH by comparing 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and hyperpolarized [1-13C]pyruvate MR spectroscopy imaging (MRSI) to chemical exchange saturation transfer (CEST) MRI measurements of tumor pH. METHODS: 106 C6 glioma cells were implanted in the brains of male Wistar rats (N = 11) using stereotactic surgery. A 60-min PET acquisition after a bolus of FDG was performed at 11-13 days post implantation, and standardized uptake value (SUV) was calculated. CEST measurements were acquired the following day before and during constant infusion of glucose solution. Tumor intracellular pH (pHi) was evaluated using amine and amide concentration-independent detection (AACID) CEST MRI. The change of pHi (∆pHi) was calculated as the difference between pHi pre- and during glucose infusion. Rats were imaged immediately with hyperpolarized [1-13C]pyruvate MRSI. Regional maps of the ratio of Lac:Pyr were acquired. The correlations between SUV, Lac:Pyr ratio, and ∆pHi were evaluated using Pearson's correlation. RESULTS: A decrease of 0.14 in pHi was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pHi within the tumor (ρ = 0.83, P = 0.01) and peritumoral region (ρ = 0.76, P = 0.028) were observed. No significant correlations were found between tumor SUV and ∆pHi within the tumor (ρ = - 0.45, P = 0.17) and peritumor regions (ρ = - 0.6, P = 0.051). CONCLUSION: AACID detected the changes in pHi induced by glucose infusion. Significant correlations between tumor glycolytic measurement of Lac:Pyr and tumoral and peritumoral pHi and ∆pHi suggest the intrinsic relationship between tumor glycolytic metabolism and the tumor pH environment as well as the peritumor pH environment.

Attenuation correction for PET/MRI to measure tracer activity surrounding total knee arthroplasty.

BACKGROUND: Positron emission tomography (PET) in combination with magnetic resonance imaging (MRI) could allow inflammatory complications near total knee arthroplasty (TKA) to be studied early in their development. However, attenuation of the PET signal by the metal TKA implants imparts substantial error into measurements of tracer activity, and conventional MR-based attenuation correction (AC) methods have large signal voids in the vicinity of metal implants. PURPOSE: To evaluate a segmentation-based AC approach to measure tracer uptake from PET/MRI scans near TKA implants. METHODS: A TKA implant (Triathlon, Stryker, Mahwah, USA) was implanted into a cadaver. Four vials were filled with [18F]fluorodeoxyglucose with known activity concentration (4.68 MBq total, 0.76 MBq/mL) and inserted into the knee. Images of the knee were acquired using a 3T PET/MRI system (Biograph mMR, Siemens Healthcare, Erlangen, Germany). Models of the implant components were registered to the MR data using rigid-body transformations and the other tissue classes were manually segmented. These segments were used to create the segmentation-based map and complete the AC. Percentage error of the resulting measured activities was calculated by comparing the measured and known amounts of activity in each vial. RESULTS: The original AC resulted in a percentage error of 64.1% from the known total activity. Errors in the individual vial activities ranged from 40.2 to 82.7%. Using the new segmentation-based AC, the percentage error of the total activity decreased to 3.55%. Errors in the individual vials were less than 15%. CONCLUSIONS: The segmentation-based AC technique dramatically reduced the error in activity measurements that result from PET signal attenuation by the metal TKA implant. This approach may be useful to enhance the reliability of PET/MRI measurements for numerous applications.

Imaging Biomarkers in Prostate Stereotactic Body Radiotherapy: A Review and Clinical Trial Protocol.

Advances in imaging have changed prostate radiotherapy through improved biochemical control from focal boost and improved detection of recurrence. These advances are reviewed in the context of prostate stereotactic body radiation therapy (SBRT) and the ARGOS/CLIMBER trial protocol. ARGOS/CLIMBER will evaluate 1) the safety and feasibility of SBRT with focal boost guided by multiparametric MRI (mpMRI) and 18F-PSMA-1007 PET and 2) imaging and laboratory biomarkers for response to SBRT. To date, response to prostate SBRT is most commonly evaluated using the Phoenix Criteria for biochemical failure. The drawbacks of this approach include lack of lesion identification, a high false-positive rate, and delay in identifying treatment failure. Patients in ARGOS/CLIMBER will receive dynamic 18F-PSMA-1007 PET and mpMRI prior to SBRT for treatment planning and at 6 and 24 months after SBRT to assess response. Imaging findings will be correlated with prostate-specific antigen (PSA) and biopsy results, with the goal of early, non-invasive, and accurate identification of treatment failure.

Glial activation positron emission tomography imaging in radiation treatment of breast cancer brain metastases.

Brain metastases affect more breast cancer patients than ever before due to increased overall patient survival with improved molecularly targeted treatments. Approximately 25-34% of breast cancer patients develop brain metastases in their lifetime. Due to the blood-brain barrier (BBB), the standard treatment for breast cancer brain metastases (BCBM) is surgery, stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). At the cost of cognitive side effects, WBRT has proven efficacy in treating brain metastases when used with local therapies such as SRS and surgery. This review investigated the potential use of glial activation positron emission tomography (PET) imaging for radiation treatment of BCBM. In order to put these studies into context, we provided background on current radiation treatment approaches for BCBM, our current understanding of the brain microenvironment, its interaction with the peripheral immune system, and alterations in the brain microenvironment by BCBM and radiation. We summarized preclinical literature on the interactions between glial activation and cognition and clinical studies using translocator protein (TSPO) PET to image glial activation in the context of neurological diseases. TSPO-PET is not employed clinically in assessing and guiding cancer therapies. However, it has gained traction in preclinical studies where glial activation was investigated from primary brain cancer, metastases and radiation treatments. Novel glial activation PET imaging and its applications in preclinical studies using breast cancer models and glial immunohistochemistry are highlighted. Lastly, we discuss the potential clinical application of glial activation imaging to improve the therapeutic ratio of radiation treatments for BCBM.

A Human-derived Dual MRI/PET Reporter Gene System with High Translational Potential for Cell Tracking.

PURPOSE: Reporter gene imaging has been extensively used to longitudinally report on whole-body distribution and viability of transplanted engineered cells. Multi-modal cell tracking can provide complementary information on cell fate. Typical multi-modal reporter gene systems often combine clinical and preclinical modalities. A multi-modal reporter gene system for magnetic resonance imaging (MRI) and positron emission tomography (PET), two clinical modalities, would be advantageous by combining the sensitivity of PET with the high-resolution morphology and non-ionizing nature of MRI. PROCEDURES: We developed and evaluated a dual MRI/PET reporter gene system composed of two human-derived reporter genes that utilize clinical reporter probes for engineered cell detection. As a proof-of-concept, breast cancer cells were engineered to co-express the human organic anion transporter polypeptide 1B3 (OATP1B3) that uptakes the clinical MRI contrast agent gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA), and the human sodium iodide symporter (NIS) which uptakes the PET tracer, [18F] tetrafluoroborate ([18F] TFB). RESULTS: T1-weighted MRI results in mice exhibited significantly higher MRI signals in reporter-gene-engineered mammary fat pad tumors versus contralateral naïve tumors (p < 0.05). No differences in contrast enhancement were observed at 5 h after Gd-EOB-DTPA administration using either intravenous or intraperitoneal injection. We also found significantly higher standard uptake values (SUV) in engineered tumors in comparison to the naïve tumors in [18F]TFB PET images (p < 0.001). Intratumoral heterogeneity in signal enhancement was more conspicuous in relatively higher resolution MR images compared to PET images. CONCLUSIONS: Our study demonstrates the ability to noninvasively track cells engineered with our human-derived dual MRI/PET reporter system, enabling a more comprehensive evaluation of transplanted cells. Future work is focused on applying this tool to track therapeutic cells, which may one day enable the broader application of cell tracking within the healthcare system.

Short-duration dynamic [18F]DCFPyL PET and CT perfusion imaging to localize dominant intraprostatic lesions in prostate cancer: validation against digital histopathology and comparison to [18F]DCFPyL PET/MR at 120 minutes.

PURPOSE: Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [18F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images. METHODS: Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [18F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance. RESULTS: [18F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUVLate and a model combining Ki and k4 of [18F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of < 10%. Compared to digital histopathology, the detected DILs had a mean dice similarity coefficient of 0.8 for the Ki and k4 model and 0.7 for SUVLate. CONCLUSIONS: We have validated using co-registered digital histopathological images that parameters from kinetic analysis of 22-min dynamic [18F]DCFPyL PET can accurately localize DILs in PCa for targeting of biopsy, radiotherapy, and focal ablative therapies. Short-duration dynamic [18F]DCFPyL PET was not inferior to SUVLate in this diagnostic task. CLINICAL TRIAL REGISTRATION NUMBER: NCT04009174 (ClinicalTrials.gov).

Prostate specific membrane antigen positron emission tomography for lesion-directed high-dose-rate brachytherapy dose escalation.

BACKGROUND AND PURPOSE: Prostate specific membrane antigen positron emission tomography imaging (PSMA-PET) has demonstrated potential for intra-prostatic lesion localization. We leveraged our existing database of co-registered PSMA-PET imaging with cross sectional digitized pathology to model dose coverage of histologically-defined prostate cancer when tailoring brachytherapy dose escalation based on PSMA-PET imaging. MATERIALS AND METHODS: Using a previously-developed automated approach, we created segmentation volumes delineating underlying dominant intraprostatic lesions for ten men with co-registered pathology-imaging datasets. To simulate realistic high-dose-rate brachytherapy (HDR-BT) treatments, we registered the PSMA-PET-defined segmentation volumes and underlying cancer to 3D trans-rectal ultrasound images of HDR-BT cases where 15 Gray (Gy) was delivered. We applied dose/volume optimization to focally target the dominant intraprostatic lesion identified on PSMA-PET. We then compared histopathology dose for all high-grade cancer within whole-gland treatment plans versus PSMA-PET-targeted plans. Histopathology dose was analyzed for all clinically significant cancer with a Gleason score of 7or greater. RESULTS: The standard whole-gland plans achieved a median [interquartile range] D98 of 15.2 [13.8-16.4] Gy to the histologically-defined cancer, while the targeted plans achieved a significantly higher D98 of 16.5 [15.0-19.0] Gy (p = 0.007). CONCLUSION: This study is the first to use digital histology to confirm the effectiveness of PSMA-PET HDR-BT dose escalation using automatically generated contours. Based on the findings of this study, PSMA-PET lesion dose escalation can lead to increased dose to the ground truth histologically defined cancer.

Blood-brain barrier permeability in survivors of immune-mediated thrombotic thrombocytopenic purpura: a pilot study.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity < 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) × 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of -0.312 mL/min/100 g (95% confidence interval: -0.4729 to -0.1510; P = .0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications.

Improved PET/MRI accuracy by use of static transmission source in empirically derived hardware attenuation correction.

BACKGROUND: Accurate quantification of radioactivity, measured by an integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) system, is still a challenge. One aspect of such a challenge is to correct for the hardware attenuation, such as the patient table and radio frequency (RF) resonators. For PET/MRI systems, computed tomography (CT) is commonly used to produce hardware attenuation correction (AC) maps, by converting Hounsfield units (HU) to a linear attenuation coefficients (LAC) map at the PET energy level 511 keV, using a bilinear model. The model does not address beam hardening, nor higher density materials, which can lead to inaccurate corrections. PURPOSE: In this study, we introduce a transmission-based (TX-based) AC technique with a static Germanium-68 (Ge-68) transmission source to generate hardware AC maps using the PET/MRI system itself, without the need for PET or medical CT scanners. The AC TX-based maps were generated for a homogeneous cylinder, made of acrylic as a validator. The technique thereafter was applied to the patient table and posterior part of an RF-phased array used in cardiovascular PET/MRI imaging. The proposed TX-based, and the CT-based, hardware maps were used in reconstructing PET images of one cardiac patient, and the results were analysed and compared. RESULTS: The LAC derived by the TX-based method for the acrylic cylinder is estimated to be 0.10851 ± 0.00380 cm-1 compared to the 0.10698 ± 0.00321 cm-1 theoretical value reported in the literature. The PET photon counts were reduced by 8.7 ± 1.1% with the patient table, at the region used in cardiac scans, while the CT-based map, used for correction, over-estimated counts by 4.3 ± 1.3%. Reconstructed in vivo images using TX-based AC hardware maps have shown 4.1 ± 0.9% mean difference compared to those reconstructed images using CT-based AC. CONCLUSIONS: The LAC of the acrylic cylinder measurements using the TX-based technique was in agreement with those in the literature confirming the validity of the technique. The over-estimation of photon counts caused by the CT-based model used for the patient table was improved by the TX-based technique. Therefore, TX-based AC of hardware using the PET/MRI system itself is possible and can produce more accurate images when compared to the CT-based hardware AC in cardiac PET images.

Multimodality In Vivo Imaging of Perfusion and Glycolysis in a Rat Model of C6 Glioma.

PURPOSE: Chemical exchange saturation transfer MRI using an infusion of glucose (glucoCEST) is sensitive to the distribution of glucose in vivo; however, whether glucoCEST is more related to perfusion or glycolysis is still debatable. We compared glucoCEST to computed tomography perfusion (CTP), [18F] fluorodeoxyglucose positron emission tomography (FDG-PET), and hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy imaging (MRSI) in a C6 rat model of glioma to determine if glucoCEST is more strongly correlated with measurements of perfusion or glycolysis. METHODS: 106 C6 glioma cells were implanted in Wistar rat brains (n = 11). CTP (including blood volume, BV; blood flow, BF; and permeability surface area product, PS) and FDG-PET standardized uptake value (SUV) were acquired at 11 to 13 days post-surgery. GlucoCEST measurements (∆CEST) were acquired the following day on a 9.4 T MRI before and after an infusion of glucose solution. This was followed by MRSI on a 3.0 T MRI after the injection of hyperpolarized [1-13C] pyruvate to generate regional maps of the lactate:pyruvate ratio (Lac:Pyr). Pearson's correlations between glucoCEST, CTP, FDG-PET, and Lac:Pyr ratio were evaluated. RESULTS: Tumors had significantly higher SUV, BV, and PS than the contralateral brain. Tumor ∆CEST was most strongly correlated with CTP measurements of BV (ρ = 0.74, P = 0.01) and PS (ρ = 0.55, P = 0.04). No significant correlation was found between glycolysis measurements of SUV or Lac:Pyr with tumor ∆CEST. PS significantly correlated with SUV (ρ = 0.58, P = 0.005) and Lac:Pyr (ρ = 0.75, P = 0.005). BV significantly correlated with Lac:Pyr (ρ = 0.57, P = 0.02), and BF significantly correlated with SUV (ρ = 0.49, P = 0.02). CONCLUSION: This study determined that glucoCEST is more strongly correlated to measurements of perfusion than glycolysis. GlucoCEST measurements have additional confounds, such as sensitivity to changing pH, that merit additional investigation.

An evaluation of the diagnostic equivalence of 18F-FDG-PET between hybrid PET/MRI and PET/CT in drug-resistant epilepsy: A pilot study.

OBJECTIVE: Hybrid PET/MRI may improve detection of seizure-onset zone (SOZ) in drug-resistant epilepsy (DRE), however, concerns over PET bias from MRI-based attenuation correction (MRAC) have limited clinical adoption of PET/MRI. This study evaluated the diagnostic equivalency and potential clinical value of PET/MRI against PET/CT in DRE. MATERIALS AND METHODS: MRI, FDG-PET and CT images (n = 18) were acquired using a hybrid PET/MRI and a CT scanner. To assess diagnostic equivalency, PET was reconstructed using MRAC (RESOLUTE) and CT-based attenuation correction (CTAC) to generate PET/MRI and PET/CT images, respectively. PET/MRI and PET/CT images were compared qualitatively through visual assessment and quantitatively through regional standardized uptake value (SUV) and z-score assessment. Diagnostic accuracy and sensitivity of PET/MRI and PET/CT for SOZ detection were calculated through comparison to reference standards (clinical hypothesis and histopathology, respectively). RESULTS: Inter-reader agreement in visual assessment of PET/MRI and PET/CT images was 78 % and 81 %, respectively. PET/MRI and PET/CT were strongly correlated in mean SUV (r = 0.99, p < 0.001) and z-scores (r = 0.92, p < 0.001) across all brain regions. MRAC SUV bias was <5% in most brain regions except the inferior temporal gyrus, temporal pole, and cerebellum. Diagnostic accuracy and sensitivity were similar between PET/MRI and PET/CT (87 % vs. 85 % and 83 % vs. 83 %, respectively). CONCLUSION: We demonstrate here that PET/MRI with optimal MRAC can yield similar diagnostic performance as PET/CT. Nevertheless, further exploration of the potential added value of PET/MRI is necessary before clinical adoption of PET/MRI for epilepsy imaging.

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat.

BACKGROUND: Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer's disease and acute subcortical stroke. METHODS: Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. RESULTS: [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). CONCLUSION: TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.